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. 2019 Aug 30;14(8):e0221972.
doi: 10.1371/journal.pone.0221972. eCollection 2019.

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

Iris Bekkering  1   2 , Mariëtte Leeuwerke  1 , Jozien C Tanis  1   2 , Mirthe H Schoots  3 , Rikst Nynke Verkaik-Schakel  1 , Torsten Plösch  1 , Caterina M Bilardo  1 , Jasper J H Eijsink  1 , Arend F Bos  2 , Sicco A Scherjon  1
Affiliations

Differential placental DNA methylation of VEGFA and LEP in small-for-gestational age fetuses with an abnormal cerebroplacental ratio

Iris Bekkering et al. PLoS One. .

Abstract

Background: In Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes.

Methods: We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing.

Results: Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes.

Conclusions: VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Methylation of VEGFA for normal and abnormal CPR.
Mean shown for CpG-1 (-309) & CpG-2 (-313) and median for CpG-3 (-331). And C; boxplot with 5–95 percentile whiskers mean methylation of VEGFA CpG-1 (-309). Double asterisk (**) indicates significance of p <0.01.
Fig 2
Fig 2. Methylation of LEP for normal and abnormal CPR.
A; Methylation levels of LEP represented relative to the Transcription Start Site (TSS). CpG-1 (-127), CpG-2 (-123), CpG-3 (-118), CpG-4 (-115), CpG-5 (-100), CpG-6 (-95), CpG-7 (-85), CpG-8 (-74), CpG-9 (-71), CpG-10 (-62), CpG-11 (-51), CpG-12 (-38), CpG-13 (-33). Values are mean or median methylation as given in S1 Table. BC; boxplots with 5–95 percentile whiskers. B; Mean methylation of LEP CpG-2 (-123). Normal CPR (N = 20) Abnormal CPR (N = 14). C; Median methylation of LEP CpG-11 (-51). Asterisk (*) indicates significance of p <0.05.
Fig 3
Fig 3. Spearman correlation coefficients (rho) and associated p-values provided for the association between and DNA methylation and CPR z-score.
VEGFA CpG-1 (A), LEP CpG-11 (B). Asterisk (*) indicates significance of p <0.05.
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References

    1. Wladimiroff JW, Tonge HM, Stewart B, Reuss A. Severe intrauterine growth retardation; assessment of its origin from fetal arterial flow velocity waveforms. Eur J Obstet Gynecol Reprod Biol. 1986;22: 23–28. 10.1016/0028-2243(86)90086-9 - DOI - PubMed
    1. Broek AJM Van Den, Kok JH, Houtzager BA, Scherjon SA. Behavioural problems at the age of eleven years in preterm-born children with or without fetal brain sparing: A prospective cohort study. Early Hum Dev. 2010;86: 379–384. 10.1016/j.earlhumdev.2010.04.007 - DOI - PubMed
    1. Beukers F, Aarnoudse-Moens CSH, van Weissenbruch MM, Ganzevoort W, van Goudoever JB, van Wassenaer-Leemhuis AG. Fetal Growth Restriction with Brain Sparing: Neurocognitive and Behavioral Outcomes at 12 Years of Age. J Pediatr. 2017;188: 103–109. 10.1016/j.jpeds.2017.06.003 - DOI - PubMed
    1. Miller SL, Huppi PS, Mallard C. The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome. J Physiol. 2016;594: 807–823. 10.1113/JP271402 - DOI - PMC - PubMed
    1. Koukoura O, Sifakis S, Spandidos DA. DNA methylation in the human placenta and fetal growth (review). Mol Med Rep. 2012;5: 883–889. 10.3892/mmr.2012.763 - DOI - PMC - PubMed